The goal of this project is to extend the development of a novel compound that can reprogram memory T lymphocytes to induce tolerance in allergic rhinitis (AR). AR is one of the most common chronic diseases in the United States (US) and is estimated to affect more than 50 million people [1,2]. As a result, the annual US economic burden of AR exceeds $12 billion, with half of these costs attributed to prescription medications [3]. Globally, over 400 million people suffer from AR, with an estimated economic burden of greater than $20B [4] and the prevalence continues to increase. Allergic rhinitis is a chronic inflammatory disease of the upper airway. It occurs when an allergen, such as dander, dust, or pollen is inhaled by an individual with a sensitized immune system. The allergic inflammation can result in nasal congestion, headaches, hoarseness, postnasal drip, tonsillitis, sore throat, sneezing and stuffy nose. Due to recurring inflammation o the sinuses, AR patients are known to develop chronic rhinosinusitis. Moreover, patients suffering from AR are more likely to develop asthma later in life [5] and to demonstrate less control of asthma attacks compared to asthma patients without AR [6,7]. Finally, AR can impact quality of sleep, contributing to fatigue, irritability, memory deficits, daytime sleepiness and depression. For adults, AR symptoms impact adult emotional well-being and work productivity [8]. For children, it can impact the ability to learn in school, socialize and play sports [9]. Recently, we discovered when memory T-cells encounter antigen in the context of a multimeric form of high- molecular weight hyaluronan (HMW-HA), a natural polysaccharide present in healing tissues, they develop a tolerance-inducing TR1 phenotype and produce high amounts of interleukin-10 (IL-10). Our studies have demonstrated that multimeric HMW-HA promotes IL-10 production via CD44 dependent MAP kinase signaling [10-13]; in contrast, we have found monomeric HMW-HA does not. Thus, based on this research, a novel multimeric therapeutic called XHA was developed by chemically cross-linking HMW-HA to maintain integrity and efficacy and to prolong in vivo half-life. Using intranasal delivery of a 0.1% XHA solution, we have generated antigen-specific TR1 cells in vivo and inhibited disease in a mouse model of airway hypersensitivity. The overall goal is to develop XHA as a therapeutic that induces tolerance against ambient aeroallergens, reversing symptoms and inflammation associated with AR. The aims of the proposed studies are to: 1) establish GMP-compatible XHA scale-up production and QA/QC protocols, 2) determine the optimal dosing of XHA to maximize inhibition of nasal allergic rhinitis, and 3) demonstrate that at optimal dosing XHA is able to reverse established allergic rhinitis.